The acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality around the world. In the United States alone there are 150,000 cases per year. Although there have been significant scientific advances in understanding the clinical and pathophysical aspects of the syndrome, there is as yet no specific therapy for ARDS. Moreover, although major risk factors for the development of ARDS include sepsis, aspiration, and multiple trauma, only a minority of patients with these risk factors develop ARDS. Individual differences in susceptibility to chronic disease have been a subject of active molecular epidemiologic investigations for the past decade. In particular, risk factors for cancer conferred by heritable polymorphisms and various metabolic functions have been reported. More recently, a polymorphism of endothelial nitrate oxide synthase has been associated with an increased susceptibility to coronary-artery disease, and polymorphisms in GSTM1 have been associated with an increased risk of developing asbestosis. A recent study of tumor necrosis factor (TNF) polymorphisms has been associated with poor outcome in ARDS. The purpose of this proposal, therefore, is to examine the association between specific polymorphisms in several genes coding for specific inflammatory responses and for surfactant protein and their potential association with increased susceptibility to ARDS. Our first objective will be to assess the role of candidate-gene polymorphisms as risk factors for ARDS in a case-control study. Our second objective will be to assess the relationship between genotype and phenotype for candidate markers in cases and controls. Our third objective will be to assess the role of these polymorphisms in clinical outcome (survival, recovery) using patients from both the proposed case-control study and the multicenter case series and clinical trial sponsored by the NHLBI ARDS network. By combining both a large case-control study and case series from the network, we have the advantages of sufficient case ascertainment, statistical power, diagnostic standardization, uniform outcome criteria and study efficiency. Overall, the results of this study will provide new insights into the epidemiology of ARDS and allow for possible preventive strategies as well as possible modifications of therapeutic interventions for the Network Phase III trials.